Inorganic-polymer complexes for the controlled release of compounds including medicinals

ABSTRACT

The production and use of inorganic-polymer complexes for the controlled release of compounds including medicinals are disclosed. Advantageously, the inorganic used is calcium sulfate.

FIELD OF THE INVENTION

[0001] This invention relates generally to the production and use ofinorganic-polymer complexes for the controlled release of compoundsincluding medicinals.

BACKGROUND OF THE INVENTION

[0002] Systemic antibiotic treatment is often unsatisfactory in cases ofosteomylelitis as well as infections in devitalized tissue, avascularscar tissue, and other areas with insufficient blood supply. Increasingblood levels of antibiotics can result in toxicity. For example,aminoglycosides can produce ototoxicity and nephrotoxicity. Anotherproblem with long-term systemic treatment with antibiotics is theselection of drug-resistant mutants. In poorly vascularized areas, theinfectious organism may encounter concentrations below the minimumlethal concentration which provides the opportunity for selection of aresistant form. Also, in large-animal veterinary practice, the cost ofthe antibiotic for systemic use can be an issue.

[0003] Antibiotic formulations of polymethylmethacrylate have beenemployed as antiseptic bone cement and as beads either free or attachedto a wire which is used for percutaneous removal [H. W. Bucholz. et al.Chiburg. 43. 446 (1970)]. PMMA is not bio-erodible.

[0004] An alternative is plaster of Paris (POP) which has been usedwithout matrix biopolymers or medicinal complexing agents asCaSO₄.1/2H₂O [D. Mackey. et al. Clin. Orthop. 167, 263 (1982); and G. W.Bowyer. et al. J. Trauma. 36, 331 (1994)]. Polymethylmethacrylate andPOP have been compared with regard to release profiles. Release ratesfrom POP tend to be very fast.

[0005] Both polymethylmethacrylate and POP can be used to producedimensionally stable beads and other structures. The acrylate cements orbeads are formed by mixing pre-formed polymethylmethacrylate polymer,methylmethacrylate monomer, and a free-radical initiator. An exothermicreaction ensues which results in matrix temperatures as high as 100° C.Many antibiotics such as polymyxin and tetracycline are inactivated bythese conditions [G. J. Popham, et al. Orth. Rev., 20, 331 (1991)]. Asmentioned above, polymethylmethacrylate is biocompatible but notresorbable. Therefore, beads used to treat local infection must beretrieved by surgery which is accompanied by the risk of reinfection.

[0006] POP beads or pellets are resorbable but show inferior drugrelease profiles [G. W. Bowyer. et al. J. Trauma, 36, 331 (1994)].

[0007] Compositions containing hyaluronic acid have been used fortopical administration of pharmacological substances [F. Della Valle. etal. U.S. Pat. No. 5,166,331 and U.S. Pat. No. 4,736,024].

OBJECTS OF THE INVENTION

[0008] It is an object of the invention to provide a safe resorbabledelivery system which enables controlled release of medicinals.

[0009] It is an object of the invention to provide a delivery systemwith controllable setting time.

[0010] It is a further object of the invention to provide a deliverysystem which is an injectable liquid which solidifies in a timely wayonce in place.

SUMMARY OF THE INVENTION

[0011] The subject invention relates to a delivery system comprising:

[0012] a) an inorganic compound capable of undergoing hydration and/orcrystallization. and

[0013] b) a matrix polymer, and/or

[0014] c) a complexing agent.

[0015] In another embodiment, the system comprises a complexing agentand a medicinal. Included within the invention are methods of producingsustained release of a medicinal in a mammal by administering the systemwith a medicinal to a mammal. A still further embodiment of theinvention is a method of diagnosing disease in a mammal by administeringa radiopaque matrix to the mammal.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The subject invention relates to a resorbable matrix withfavorable release kinetics. Inorganic compounds such as CaSO₄.1/2H₂O canbe combined with biopolymer in the presence of a bioactive agentincluding medicinals to produce a matrix.

[0017] In addition to the inorganic compound there are:

[0018] (i) a matrix polymer, and/or (ii) a complexing agent. As usedherein, the term “matrix polymer” refers to a polymer (often abiopolymer) which series to control the erosion rate, setting time, andinfluences the release profile by raising the viscosity of the medium inthe pores and channels of the delivery system. As used herein, the term“complexing agent,” refers to an agent (often a biopolymer), which isused to form a salt or conjugate with the active agent which in effectraises the molecular weight of the active agent and lowers its rate ofefflux. The complexing agent is typically a small molecule capable ofaggregation which has affinity for the active agent. Pharmacologicallyacceptable hydrophobic medicinal complexing agents include proteins suchas albumin, lipids or cyclodextrins which can be used to complex neutralmedicinal molecules or charged molecules which contain an apolar moiety.Liposomes containing a medicinal can be entrapped within the calciumsulfate matrix.

[0019] The reaction scheme for forming a matrix including a medicinal isshown below:

[0020] The consistency and viscosity of the slurry is dependent on theamount and nature of the matrix biopolymer. The slurry can be injectedwith subsequent formation of a solid in vivo.

[0021] A medicinal can exist in the inorganic-biopolymer complex eitherfree or complexed to the medicinal complexing agent. The free compoundis released relatively fast. The complexed medicinal is releasedrelatively slowly often contingent on the bio-erosion of theinorganic-biopolymer complex. Antibiotics and local anesthetics are usedto illustrate this principle:

[0022] The resorbable inorganic-biopolymer complex can contain freeantibiotic (e.g., as the sodium salt) or in the form of a biopolymercomplex with a polycation such as a polypeptide such as polymyxin B oran aminoglycoside. Lidocaine is conveniently employed as thehydrochloride, the free base, or complexed as the salt of chondroitinsulfate or polyglutamate.

[0023] I. General Considerations

[0024] The delivery system of the subject invention for use withmedicinals must meet the following requirements:

[0025] 1 Safety—non-toxic, non-immunogenic, non-pyrogenic,non-allergenic.

[0026] 2. Resorbability—all components should be either assimilable orreadily excreted.

[0027] 3. Stability—the matrix should be sterilizable and precursorsshould have an acceptable shelf-life. Cast forms should be dimensionallystable.

[0028] 4. Compatibility—the materials and the preparative conditionsshould not alter the chemistry or activity of the medicinal.

[0029] 5. Programmability—the residence time and release profile shouldbe adjustable.

[0030] There are typically two or three components in theinorganic-polymer complex matrix—

[0031] 1. An inorganic compound, for example. CaSO₄.1/2H₂O

[0032] 2. Matrix polymer, for example, hyaluronic acid or dextran

[0033] 3. Complexing agent, for example, chondroitin sulfate, cationicpolypeptide, or cyclodextrin.

[0034] Inorganic Compounds

[0035] Calcium sulfate.1/2H₂O (hemihydrate) is the preferred inorganiccomponent. The hemihydrate takes up water and crystallizes as the higherhydrate. Unadulterated calcium sulfate matrix exhibits poor drug releaseprofiles. With matrix polymers and complexing agent-active agentcomplexes the release profiles are improved. Other inorganics may beemployed such as calcium silicates, aluminates, hydroxides and,orphosphates (see pages 72, 95, 327 in Reference Book of Inorganic Chemist(1951 ) Latimer. W. H., and Hildebrand. J. M., Macmillan, N.Y., herebyincorporated by reference in its entirety).

[0036] The inorganic compound goes from slurry to solid in a reasonabletime period, i.e., 10 minutes-two hours. The matrix biopolymerinfluences the setting time and the release profile. Sodium salts andchloride ion act as inhibitors. Sulfate salts and calcium saltsaccelerate the solidification process. Calcium pentosan polysulfatecontaining slurries solidify faster than those containing sodium as thecounterion.

[0037] In an advantageous embodiment, the matrix has a porositysufficient to permit the influx of cells (e.g., osteocytes). See Example15.

[0038] Polymers

[0039] In order to slow the efflux of active agent. e.g., medicinal,from the dosage form, polymers, often biopolymers, are included in thematrix to raise the viscosity. Hyaluronic acid (e.g., 1-5%), proteins,e.g., collagen (gelatin), fibrinogen, which form viscous solutions(e.g.,1-30%), and dextran (e.g., 1-50%) are examples. Viscosity can bechanged as a function of time. Hydrolytic enzymes such as a protease,can be included to lower the viscosity as a function of time to speedthe efflux and compensate for the decrease in the medicinal gradient.This feature provides for a desirable release profile. For medicinaluses, biopolymers (polymers of biological origin) are advantageouslyemployed.

[0040] Complexing Agents

[0041] To make biopolymer-medicinal complexes for use in parenteralmatrices, polymers which are known to be safe are employed. Polymersuseful for this purpose include, but are not limited to, the following:

[0042] glycosaminoglycans such as chondroitin sulfate, hyaluronic acid

[0043] polynucleotides

[0044] acidic proteins

[0045] polyglutamic acid

[0046] polyaspartic acid

[0047] pentosan polysulfate

[0048] dextran sulfate

[0049] The polymers should be assimilable for use in veterinary or humanmedicine.

[0050] In another embodiment, lower molecular weight compounds can beused as the complexing agent. For example, carboxylic acids such ascaprylic acid, undec-lenic acid, piperacillin, penicillin V. nafcillinor cefazolin.

[0051] For the complexation of anionic medicinals such as some β-lactamantibiotics advantageous polymers include polypeptide cations such aspolymyxins and aminoglycoside antibiotics such as amikacin. Formedicinals not carrying a net positive or negative charge or those thatpossess a significant amount of apolar character, neutral complexingagents are employed. Examples include cyclodextrins, Polysorb 80 andproteins which bind the medicinals. Small molecules which aggregate andbind the medicinals are alternatives. Apolar molecules which formmulti-molecular agcregates can be employed. This type is exemplified byliposomes. A series of active medicinals which possess varying degreesof apolar character can be advantageously employed with the apolarcomplexing agent. Such a series is exemplified by hydrocortisonehemisuccinate-sodium, hydrocortisone, hydrocortisone acetate, andhydrocortisone octanoate.

[0052] The rationale for using complexing agents is based on Stokes law:

D∝1/Mv

[0053] D=the diffusion coefficient

[0054] M=the molecular weight of the medicinal

[0055] v=the viscosity of the medium

[0056] Use of complexation biopolymers in effect raises the molecularweight of the medicinal. The presence of both the matrix biopolymer andmedicinal complexing agent can increase the viscosity within the matrixwhich lowers the diffusivity. Another view of the retardation of releaseconcerns the maintenance of electrical neutrality. In order for thecharged medicinal to diffuse away from the medicinal complexing agent anexternal counterion must first diffuse into the matrix and exchange forthe medicinal.

[0057] The medicinal complexins agent serves to delay the release of themedicinal. The medicinal complexing agents can be in the form of acationic polymer such as polypeptide cations. aminoglycosides, ananionic polymer such as chondroitin sulfate and a neutral compound suchas cyclodextrin or a lipid or mixture of lipids. Also, chondroitinsulfate and other polyanions can be used with a tetramethyl-lysinelinker

[0058] which is used in anhydride linkage with β-lactam antibiotics (I)or a carboxylated NSAID (II):

[0059] Use of a series of medicinal complexing agents of varying size isillustrated by the example of penicillin G ionically complexed toprogressively larger amines: procaine, beizathine, polymyxin, and otherpolypeptide cations. Cationic medicinals may be analogously bound toprogressively larger carboxylate (sulfate) containing compounds. Anenzymatic direst of chondroitin sulfate constitutes a random series ofsizes and is conveniently prepared.

[0060] In one embodiment of the invention, there is a complexing agentand a medicinal only (without an inorganic): see e.g., Table 1compositions E, H, J, K, L and O. In another embodiment of theinvention, there is a matrix polymer and a medicinal only (without aninorganic), for example, hyaluronic acid and a medicinal such as anantibiotic or anesthetic. Complexing agents for non-medicinals arediscussed in section V “Non-medical Applications.”

[0061] Advantageous delivery systems of the invention are shown in Table1 below: TABLE 1 Complexing Formulation CaSO₄ 1/2H₂O Matrix polymeragent Medicinal A 1 g HA - 0.6 ml (2%)  50 mg NF R/100 mgIa B 1 gDextran - 0.6 ml(20%) lecithin - 100 mg  50 mg NF R/100 mgIa C 1 g HA,0.6 ml (2%) polyglutamic 100 mg lidocaine acid D 1 g HA, 0.6 ml (2%)chon S 100 mg amikacin E — HA, 0.6 ml (2%) chon S Amikacin 100 mg F 1 gDextran - 6 ml (20%) polymyxin Cef 100 mg HA, 0.6 ml (2%) G 1 g HA, 0.6ml (2%) 500 mg HC (10% a.i.) H — HA, 0.6 ml (2%) 500 mg HC (10% a.i.) I1 g HA, 0.6 ml (2%)  50 mg cis-platin J — HA, 0.6 ml (2%) chon SLidocaine 100 mg K — HA, 0.6 ml (2%) chon S Morphine 100 mg L — HA, 0.6ml (2%) chon S Hydromorphone 100 mg M 1 g HA, 0.6 ml (2%)  50 mg Imip N1 g HA, 0.6 ml (2%)  5 mg BMP-2 O — HA, 0.6 ml (2%) polymyxin 100 mgImip P 1 g — 0.6 ml chon S lidocaine 24 mg Q .5 g HA, 1 ml (2%) HA R* 1g Dextran 200 mg — Lidocaine 100 mg (solid) (solid) S 1 g Gelatin (10%)0.6 ml — Lidocaine 100 mg (solid)

[0062] II. Production of the Inorganic-Biopolymer Complex-MedicinalMatrix and Modes of Administration

[0063] The basis for formation of the inorganic-biopolymer complexmatrix can be expressed in the following reaction:

[0064] The drug, free and complexed to a medicinal complexing agent, isconveniently mixed with calcium sulfate as a finely ground solid. Thematrix biopolymer is included to influence the setting time and the drugrelease profile.

[0065] The setting time can be adjusted so that the user can administerthe inorganic-biopolymer complex matrix in the form of a liquid using asyringe with a 23 gauge needle or larger. The matrix will solidify soonthereafter. It is convenient to transfer the slurry to the barrel of asyringe using a spatula or second syringe. The plunger is inserted andthe inorganic-biopolymer complex matrix is injected after expulsion ofair. Salts of fatty acids can be included to facilitate release from themold, e.g., 1-3% calcium stearate. Subcutaneous injections are routinelydone with a syringe fitted with a 25-gauge needle. Dispensing into moldscan be accomplished using a syringe fitted with a blunt needle or insome cases a pipette. The liquid injection can be s.c., i.m., or i.p.Advantageously, the administration is done by parenteral injection.

[0066] Administration of the solid matrix can be by surgical implant,oral, i.p., i.a. or p.a. Specific sites can be targeted foradministration of the medicinal such as an anesthetic oranti-inflammatory.

[0067] The drug is conveniently employed as a solid which can be finelyground and mixed with the calcium sulfate. The matrix polymer isroutinely used as a solution. In a representative formulation thefollowing proportions and ingredients are used: Ingredient AmountCalcium sulfate 1 g Drug 50 mg matrix biopolymer at 2% 0.6 ml

[0068] If the calcium sulfate amount is set at 1 g, the amount of drugused is in the range of 1-200 mg and the matrix biopolymer in the rangeof 0.4-3 ml. The concentration of the matrix biopolymer ranges from0.1-50%.

[0069] Cooling of the ingredients prior to mixing slows the reaction.Increased liquid/solid ratios tend to slow the reaction also. Lowmolecular weight alcohols, such as propanol and butanol, significantlyprolong the setting time. The influence of two matrix biopolymers isshown in Table 2.

[0070] Polyethylene glycols (PEGs) can be used to suspend medicinals andcalcium sulfate. The solidification is retarded by PEG. Chloride andsodium salts also inhibit solidification. Availability of water also isused as a means to control the rate of solidification. Silversulfadiazine cream solidifies underwater. The isopropanol diffuses outand water diffuses in where it reacts with calcium sulfate-hemihydratewhich results in hardening. The resultant material then slowly releasesthe medicinal. See Example 11. Topical formulations permit selection ofa complexing agent and/or matrix polymer of non-biological origin.Examples include polyethyleneglycol (PEG) and polyvinylpyrrolidone(PVP). TABLE 2 Change of setting time by matrix biopolymers A.Hyaluronic acid (HA) Calcium sulfate HA (%) Setting time (min) 1 g 0.6ml (0) 75 1 g 0.6 ml (.2) 60 1 g 0.6 ml (2) 20 B. Dextran Calciumsulfate Dextran (%) Setting time (min) 1 g 0.6 ml (0) 75 1 g 0.6 ml (10)15 1 g 0.6 ml (20) 25 1 g 0.6 ml (50) 80

[0071] Dextran (clinical grade) is a convenient accelerator at lowconcentrations. The solutions are less viscous than HA solutions anddextran is inexpensive.

[0072] The inorganic-biopolymer complex can be formed as spheres,granules, cylinders, tablets and beads (including microbeads) forinjection or for use in capsules. The latter can be formed by dispersingthe slurry into a rapidly stirring water-immiscible medium. The size ofthe beads can be determined by the amount and nature of the surfactantand the stirring rate. Milling and sieving to produce beads (30-60 μ) isan alternative approach. For orthopedic and dental use theinorganic-biopolymer complex matrix can be molded and or carved intospecific shapes to conform to voids in bone structures. Just prior toformation of the intractable solid, the material is plastic and can beconveniently shaped to fit openings of irregular geometry.

[0073] II. Release Profile

[0074] An idealized release profile has three phases. The burst phase isnot necessary for many drugs but would be advantageous for anestheticsand antimicrobics. The maintenance, or zero-order phase, is a desirableresult of the delayed release of the complexed drug. The drop-off,referred to as the closing phase, occurs as the bioerosion process comesto a conclusion. Sub-batches of beads of varying size, drug load, andrelease profile can be blended to provide the desired release profile.

[0075] With regard to control of the release profile, one shouldconsider that the rate of diffusion is given by

rate=DA(d[m]/dx)   (1)

[0076] D=the diffusion coefficient

[0077] A=the surface area

[0078] d[m]/dx=the medicinal gradient

[0079] Also, according to Stokes Law

D∝1/Mv   (2)

[0080] D=diffusion coefficient

[0081] M=molecular weight

[0082] v=viscosity

[0083] The use of the medicinal complexing agent will change theeffective molecular weight of the medicinal. The matrix density andcomposition will influence the internal viscosity of the deliverysystem.

[0084] Simultaneous use of medicinal complexing agents of varying sizeis used advantageously. For example, penicillin G in the form of saltsof potassium, procaine, polymyxin, and aminoglycosides such as amikacincan be used. Polyanions with a range of sizes can be produced byenzymatically digesting glycosaminoglycans.

[0085] The shape of the delivery device will dictate the surface area.For example the surface area of a sphere is given by

A=47πr²   (3)

[0086] The volume of a sphere is given by $\begin{matrix}{V = {\frac{4}{3}\pi \quad r^{3}}} & (4)\end{matrix}$

[0087] Combining (3) and (4) gives

A/V=3/r   (5)

[0088] According to equation (5) as beads get smaller, the surface areaper a given volume of inorganic-biopolymer complex increases. One cc ofinorganic-biopolymer complex matrix dispersed as small beads deliversdrug faster than one cc dispersed as large beads. The desired zero-orderrelease profile can be approached by using the proper blend of beads ofvarying size.

[0089] Residence time in vivo and bio-compatibility have been assessedusing hamsters. Inorganic-biopolymer complex matrices were injected (0.3ml) subcutaneously. At timed intervals the animals were sacrificed todetermine the residence time and the condition of the injection site asjudged by histo/path analysis. All formulations were very welltolerated. The proportion of calcium sulfate or density was an importantfactor in residence time. Denser formulations lasted longer. Calciumsulfate/HA (3/2) show a residence time of 35 days. Calcium sulfate/HA(1/2) showed a residence time of 20 days. Spherical beads (3.2 mm indiameter) made of calcium sulfate/HA (1/1) lasted ten days. Beadscontaining silver benzoate lasted two weeks and were well tolerated withno toxicity to local tissues.

[0090] Another means to control the release profile involves drugprecursors. As the precursor is converted to the native compound, itsavidity (affinity) for the medicinal complexing agent decreases which inturn raises its diffusivity, thus creating a biphasic release profile.As opposed to release of a molecule that is covalently linked to apolymer, this embodiment is dependent on a change in polarity. Considerthe following:

[0091] Compound I is positively charged at physiological pH. It isstrongly bound to chondroitin sulfate. As it hydrolyzes to form.Compound II, the net charge becomes zero and as a consequence therelease is accelerated. A biphasic release profile is the result whenfree II is included in the dosage form. The release profile can becontrolled by the nature of the hydrolyzable group attached to thecarboxyl group. The hydrolyzable croup can be an ester, an anhydride orother labile functionalities.

[0092] IV. Medicinals

[0093] A. Non-Protein Drugs

[0094] The delivery systems described herein are well suited forsustained release of: an analgesic, an anesthetic, an anti-addictivepreparation (e.g., naltrexone), an anti-microbic, an antiseptic (e.gs.silver ion, and silver sulfadiazine, calcium peroxide, calciumhypochlorite), an anticoagulant, an antineooiastic, an antidepressant ananti-diabetic agent, an antihypertensive drug, an anti-inflammatoryagent, an antinauseant, an anorexic, an antiulcer drug, a cardiovasculardrug, a chondroprotective agent, a contraceptive, an antihistamine, adiuretic, a hormone antihormone, an immunosuppressive, a narcoticdetoxification agent, a uricosuric agent, and a wound healing promoter.

[0095] A logical alternative to systemic treatment is to employ deliverysystems for local release of antibiotics. In this case, levels muchgreater than the minimum lethal concentration can be achieved in thetherapeutic compartment while blood levels remain low. Inorganicbiopolymer complexes can be implanted as beads after surgicaldebridement or the matrix can be injected as a liquid with subsequentsolidification.

[0096] The inorganic-biopolymer complexes containing antibiotics areespecially useful in filling cavities in bone produced by osteomyelitis.Placement of antibiotic-inorganic-biopolymer complexes in the vicinityof infected bone or other tissue results in eradication of themicro-organism and permits aseptic healing accompanied by resorption ofthe inorganic-biopolymer complex. When treating bone lesions, bonemorphogenic proteins can also be included to promote growth of new bone.

[0097] Inorganic biopolymer complexes are effective for treatment ofother local infections, such as joint sepsis, surgical infections, woundinfections, uterine infections, oral-dental-periodontal infections,vaginitis, and localized abscesses. Likely infectious agents includeAeromonas, Capnocytophaga, Citrobacter, Clostridium, Edwardsiella,Eichenella, Enterobacter, Enteroccus, E. Coli. Fusobacterium, Hafnia,Kingella, Klebsiella, Morarella, Morganella, Mycobacterium, Pasturella,Peptostreptococcus, Plesimonas, Proteus, Pseudomonas, Staphylococcus,Streptococcus, and Vibrio.

[0098] An advantageous antimicrobic for treatment of localizedinfections has the following characteristics:

[0099] 1. Cidal

[0100] 2. Broad spectrum

[0101] 3. Non-toxic to local tissues

[0102] 4. Soluble and mobile, that is, readily crosses inflamedmembranes.

[0103] Antiinfectives of special interest include gentaamicin,clarithromycin, minocycline and lincomycin, amikacin, penicillin,cefazolin, ciprofloxacin, enrofloxacin, norfloxacin, silversulfadiazine, imipenem, piperacillin, nafcillin, cephalexin, vancomycin,nystatin, and amphotericin B or salts thereof. Salts ofamikacin-piperacillin and amikacin-caprylic acid are useful in that theyprovide slower release. Further, amikacin acts synergistically withpiperacillin and other β-lactams.

[0104] In high risk surgical procedures, the antibioticinorganic-biopolymer complexes can be used prophylactically. Inabdominal surgery antibiotic beads can be distributed to provideantibiotic coverage at critical points. Placing antibiotic beads underthe incision is often advantageous.

[0105] Chondroprotective agents such as chondroitin sulfate, hyaluronicacid, pentosan polysulfate and dextran sulfate can also be used,optionally with an antiinfective.

[0106] Inorganic biopolymer complexes for local delivery ofanti-inflammatory drugs hold great promise for treatment ofosteoarthritis, degenerative joint disease, and other such afflictions.Neutral and charred forms are advantageously employed together. Forexample, free hydrocortisone and hydrocortisone succinate complexed topolymyxin is a useful combination. The anti-inflammatoryinorganic-biopolymer complexes are placed adjacent to diseased joints,tendon sheaths, etc. Use can accompany arthroscopic procedures both asan injectable and as pre-formed implants. NSAIDs are also of interestincluding naproxen, and disalicylate. NSAIDS e.g., analgesics such asaspirin, and other medicinals can be formulated in tablet or capsuleform for oral administration.

[0107] Inorganic-biopolymer complexes for pain control are primarilybased on free and complexed cationic anesthetics such as lidocaine,buvicaine, bupivacaine, chloroprocaine, procaine, etidocaine,prilocaine, dezocine, hydromorphone, etc. An advantageous medicinalcomplexing agent is chondroitin sulfate. Tablets or beads are especiallyuseful following arthroscopic procedures. Implants are placed next tothe joint capsule laterally and medially. Pain relief is provided for3-5 days which obyiates or greatly reduces systemic use of narcotics.

[0108] In conjunction with surgical and diagnostic procedures, analgesiaand tranquilization can be provided by the use of a complex ofchondroitin sulfate and two bio-active compounds—fentanyl anddroperidol. The simultaneous use of free and bound forms of the activeagents provides rapid onset of the desired effects followed by sustainedrelease from the polymeric salt.

[0109] Antineoplastics such as ifosfamide, cytoxan, carboplatin,cis-platin, leuprolide, doxorubicin, carmustine, bleomycin, andfluorouracil can be formulated in inorganic-biopolymer complexes forregional chemotherapy. In situations in which locally disseminated tumoris discovered and surgical removal is deemed inadvisable, administrationof inorganic-biopolymer complex via injection is advantageous. Chargedagents can be employed as salts with medicinal complexing agents as wellas free. Neutral molecules can be formulated with cyclodextrins andemulsifiers. Also, following resection, antineoplasticinorganic-biopolymer complexes can placed in the void left by the tumoras a preventative of recurrence.

[0110] Radiopaque inorganic-biopolymer complexes can be produced byinclusion of BaSO₄, iodipamide, or other imaging agents in the complex.These formulations can be readily visualized radiographically during andafter surgical procedures.

[0111] Pre-formed beads and tablets can be used as prophylacticanti-infectives and as pain control agents. These inorganic-biopolymercomplexes are especially useful at the conclusion of orthopedicprocedures such as joint arthroscopy and arthroplasty.

[0112] B. Medicinal Proteins

[0113] As used herein, the term “medicinal” includes proteins as well assmall molecules. The term “protein” includes naturally occurringproteins, recombinant proteins, protein derivatives, chemicallysynthesized proteins, and synthetic peptides. Medicinal proteins usefulin the subject invention include colony stimulating factors (CSF)including G-CSF, GMI-CSF, and M-CSF; erythropoietin: interleukins, IL-2,IL-4, IL-6, etc; interferons; growth factors (GF) includingepidermal-GF, nerve-GF; tumor necrosis factor (TNF); hormones/bioactivepeptides; ACTH; angiotensin, atrial natriuretic peptides, bradykynin,dynorphins/endorphins/β-lipotropin fragments, enkephalin;gastrointestinal peptides including gastrin and glucacon; growth hormoneand growth hormone releasing factors; luteinizinc hormone and releasinghormone; melanocyte stimulating hormone; neurotensin; opiode peptides;oxytocin, vasopressin and vasotocin: somatostatin; substance P; clottingfactors such as Factor VIII; thrombolytic factors such as TPA andstreptokinase: enzymes used for “replacement therapy,” e.g.,glucocerebrosidase, hexoseaminidase A; and antigens used in preventativeand therapeutic vaccines such as tetanus toxoid and diptheria toxoid.Medicinal proteins of special interest appear below: Medicinal ClinicalIndication G-CSF Adjunct to myelosuppressive chemotherapy ErythropoietinAnemia kidney disease “Replacement” enzymes Heritable geneticdeficiencies of enzymes Hormones endocrine gland failure, treatment ofhormone sensitive cancers, contraception. growth promotion Cytokinessuch as colony Immunoadjuvants stimulating factors, e.g., GM-CSF,interferons, e.gs., IFN-alpha, IFN-beta, interleukins, e.gs., IL-1, IL-2and IL-6 and TNF Vaccine antigens Immunization-preventative andtherapeutic BMP-2 Bone replacement Wound healing promoters burns, traumarh-Lysozyme antimicrobic Growth Factors growth promotionInhibitors/antagonists of the above

[0114] V. Non-Medical Applications

[0115] There are agricultural and industrial applications of thematrices of the invention. The polymers are not necessarily ofbiological origin. For example, the matrix polymer can be selected fromthe following: polyethyleneglycol, polyvinylpyrrolidone,polyvinylalcohol, starch, xanthan, cellulose and cellulose derivatives(e.g., carboxymethylcellulose). Examples of non-ionic complexing agentsinclude polyoxyethylene esters and ethers, and surfactants of eitherbiological or non-biological origin. Examples of ionic complexing agentsinclude polyacrylic acid, alginic acid, dextran sulfate,polyvinylpyridine, polyvinylamine, polyethyleneimine as well assynthetic lipid compounds.

[0116] Examples of bioactive compounds which can be used with the matrixof the invention include sterilants, pheromones, herbicides, pesticides,insecticides, fungicides, algicides, growth regulators, nematicides,repellents, and nutrients.

[0117] The following Examples are illustrative, but not limiting of thecompositions and methods of the present invention. Other suitablemodifications and adaptations of a variety of conditions and parametersnormally encountered which are obvious to those skilled in the art arewithin the spirit and scope of this invention.

EXAMPLES Example 1

[0118] Preparation of a Radiopaque Norfloxacin-Inorganic-BiopolymerComplex

[0119] CaSO₄.1/2H₂O is sterilized by heating at 120° C. for 4 hours andthen divided into 1 g aliquots which are stored in individual plasticcontainers in a desiccator. Calcium sulfate(1 g), 50 mg norfloxacin, and110 mg iodipamide, all finely ground, are mixed thoroughly. To thismixture is added 0.6 ml of cold hyaluronic acid solution (2%). Theslurry is mixed to an even consistency and is loaded into the barrel ofa 3 ml syringe with a spatula. The plunger is replaced and the airexpelled. The needle is attached to the syringe and theinorganic-biopolymer complex is ready for administration or casting in amold.

Example 2

[0120] Preparation of Lidocaine Matrix

[0121] Calcium sulfate-hemihydrate (1 g) was mixed with finely grounddextran (clinical grade, 0.2 g) and lidocaine (0.1 g). The solid mixturewas then stirred with 0.6 ml of water or alternatively 0.6 ml of HA(2%). The slurry was apportioned into screw-cap vials, 0.2 ml each.After 24 hr. at room temperature, the samples were refrigerated. Therelease experiments were done at 37° C. using 1 ml of buffer per vialwith chances at 24 hr. intervals. The release buffer was PBS containing0.1% sodium azide. The concentration of lidocaine was determinedspec-ophotometrically (260 nm). See Table 3 below TABLE 3 Release ofLidocaine for Matrices with (B) and without (A) the Matrix Biopolymer.Matrix B Matrix A (11% Dextran) Day % Release Day % Release 1 85 1 24 210 2 26 3 1 3 22 4 1 4 15 5 1 5 6

Example 3

[0122] Preparation of an Inorganic-Biopolymer Complex Containing Boundand Free Amikacin

[0123] Chondroitin sulfate solution (sodium salt, 5%) is converted tothe acid form by passage over a column of Dowex-50. Assuming a residuemolecular weight of 500, a stoichiometric amount of amikacin free baseis added at 0-4° C. The pH is adjusted to 7 and the product is frozen.Alternatively, the product is freeze-dried and stored in a desiccator.Using chondroitin sulfate as the medicinal complexing agent, othercomplexes can be made by this procedure. Lidocaine, morphine,centamicin, clindamycin, and doxorubicin are examples.

[0124] Calcium sulfate (1 g) is thoroughly mixed with 50 mg ofchondroitin sulfate-amikacin (above) and 25 mg amikacin sulfate(1:2).Hyaluronic acid solution (0.6 ml, 2%) is added and the mixture handledas described in Example 1.

Example 4

[0125] Preparation of Cis-Platin Beads

[0126] Calcium sulfate (1 g) is mixed with 50 mg of finely groundcis-platin (cis-diaminedichloroplatinum). To this mixture 0.6 ml ofhyaluronic acid solution (2%) is added and the slurry is transferred toa 3 ml syringe as described in Example 1. Using a 20-gauge blunt endneedle, the inorganic-biopolymer complex is injected into a teflon moldwith spherical holes which are 3.2 mm in diameter. After 48 hours atroom temperature, the mold is split and the beads are removed with adental explorer under sterile conditions. Beads are placed in slits madesurgically around a tumor or around the site of tumor removal in aneffort to prevent recurrence.

Example 5

[0127] Preparation of Cefazolin-Inorganic-Biopolymer Complex

[0128] Polymyxin sulfate solution (10%) is cooled to 0-4° C. Astoichiometric amount of barium hydroxide solution is added to producethe free base of polymyxin and insoluble barium sulfate. Fourequivalents of cefazolin dissolved in 50% THF, are added. Aftertrituration, the suspension is filtered to remove the barium sulfate.The residue is washed to recover all of the conjugate. The solvent ofthe combined filtrate and washing is evaporated and thepolymyxin-cefazolin salt is used as the solid. Calcium sulfate (1 g) ismixed with 100 mg of polymyxin-cefazolin salt and 50 mg ofcefazolin-sodium. To this solid mixture is added 0.6 ml of hyaluronicacid (2%). The slurry is administered directly or placed in a bead ortablet mold. Other basic polypeptides, or aminoglycosides may be used inplace of polymyxin.

Example 6

[0129] Penicillin G-Inorganic-Biopolymer Complex

[0130] Penicillin G is employed simuitaneously as the salt of potassium,procaine, benzathine, and polymyxin. To 2 g of calcium sulfate is added100 mg of penicillin G-potassium plus 100 mg procaine-penicillin and 50mg each of polymyxin-penicillin and amikacin-penicillin. After thoroughmixing, 1.2 ml of 20% dextran is added and the slurry handled asdescribed above.

Example 7

[0131] An Anti-Inflammatory Inorganic-Biopolymer Complex

[0132] An apolar medicinal complexing agent such as Polysorb 80 isemployed with the following forms of hydrocortisone:

[0133] A=hydrocortisone hemisuccinate-sodium

[0134] B=hydrocortisone

[0135] C=hydrocortisone acetate

[0136] D=hydrocortisone octanoate

[0137] To 1 g of calcium sulfate is added 25 mg each of A, B, C, and Dabove. To this mixture is added 0.6 ml of 20% dextran plus 100 ul ofPolysorb 80. The slurry is handled as described above.

Example 8

[0138] Herbicide (Dinoseb) Inorganic-Polymer Composite

[0139] Dinoseb is conjugated with polyethyleneimine (PEI) using water asa solvent. To 1 ml of a PEI solution (10%) is added 200 mg of dinoseband the pH is adjusted to near neutrality. This mixture (600 mg) iscombined with 1 g of calcium sulfate and the slurry used to producebeads with a water-immiscible medium such as sesame oil. Naphthaleneacetic acid can be used in place of dinoseb to produce a long-lastingroot growth stimulator.

Example 9

[0140] Treatment of a Bone Infection

[0141] A colt, aged three months, sustained a fracture which wassuccessfully treated surgically to the point at which an infection(Enterobacter) occurred. A matrix including norfloxacin (formulation Aof Table 1) was used to treat the infection. After thorough debridementof the cavity, the void was filled with freshly prepared matrix. Nosurgical intervention was necessary after the treatment. The infectionwas eradicated and no sign of lameness appeared after 1 month.

Example 10

[0142] Preparation of the Salt, Amikacin-Chondroitin Sulfate

[0143] Chondroitin sulfate (1 g) is dissolved in 4 ml distilled water at0-4° C. TCA (1 ml ml, 32%) at 0° C. is added with stirring. The solutionis poured into 20 ml of cold ethanol; the precipitate is collected on afilter, washed and dried. One equivalent of solid amikacin (free base)is added. The solution is adjusted to pH 7.4. It can be used as is orsupplemented with amikacin sulfate.

Example 11

[0144] Preparation of Silver Sulfadiazine Cream—a Topical Anti-Infective

[0145] Component A—520 g of PEG 400 plus 200 g PEG 3350 warmed to form asingle phase (40-50°).

[0146] Component B—60 g of PVP K-30 dissolved in 170 ml of anhydrousisopropanol

[0147] Component C—20 g of silver sulfadiazine (micronized) suspended in30 ml of anhydrous isopropanol

[0148] Preparation: Components A, B, and C are mixed with stirring at45-55°. To this suspension 1 kg of calcium sulfate hemihydrate isgradually added with stirring. After mixing is complete, the product istransferred to a polypropylene vessel and stored at room temperature orbelow. The product is protected from light. Viscosity can be reduced byincreasing the relative amount of PEG 400 with regard to PEG 3350. Theconverse is also true. The weight of calcium sulfate can be reduced by50% with the other component weights held constant. The product is thenpackaged into 32 ml syringes with nozzle end caps and polyethyleneseals.

[0149] Use: Silver sulfadiazine cream is indicated for treatment ofequine thrush and white line disease. After removal of foreign matterand necrotic tissue, silver sulfadiazine cream is applied to the hoofwith concentration on the cleft of the frog. For best results thesyringe is used at 70-90°. The product is particularly advantageous forprophylactic use under shoes or pads at each shoeing.

Example 12

[0150] Silver Sulfadiazine Paste—a Topical Anti-Infective for EquineHoof Rebuilding

[0151] Component A—Silver sulfadiazine cream (above)

[0152] Component B—2% Hydroxypropyl methylcellulose in 50% alcohol(e.g., methanol, ethanol, propanol, isopropanol).

[0153] Preparation: At 30-40° two parts of Component A are mixed withone part Component B to form a thick paste. This product is stored inclosed polypropylene tubs and protected from light.

[0154] Use: Following hoof resection silver sulfadiazine paste isapplied with a spatula to fill voids and reshape the hoof. It can beused under unmedicated plastic hoof rebuilders.

Example 13

[0155] Silver Sulfadiazine Beads—a Topical Anti-Infective

[0156] Preparation: 1 g of calcium sulfate-hemihydrate and 75 mg ofsilver sulfadiazine (USP, micronized) are thoroughly mixed. A slurry ismade with 0.5 ml of Solution D. The solid which forms is ground to apowder; Particle size of <50 microns works well. Solution D is 10%dextran sulfate (sodium form, USP, MW=8,000) which is sterile filtered.

[0157] Use: These beads can be used directly on open wounds.Incorporation in a non-aqueous organic ointment base is useful; whitepetrolatum is a good choice as is polyethylene glycol basedpreparations. Suspension of these beads in propylene glycol or otherliquid vehicle is valuable for treatment of Otitis Externa.

Example 14

[0158] Silver Sulphadiazine Film—a Topical Anti-Infective

[0159] The films are cast using 2% HPMC in 50% alcohol. The silversulfadiazine beads (1-5% by wt.) described above are dispersed into theHPMC solution and the dispersion is poured onto a glass or plasticsurface. Solvent evaporation results in a very strong film. Other filmforming technologies are also applicable. These films can beincorporated into wound dressings and bandages. The film is stable inair but dissolves when in contact with water or moist tissue. Once incontact with moisture the microbeads begin releasing silversulfadiazine, which is active against a broad spectrum of bacteria,yeast, and fungi.

Example 15

[0160] Porous Orthopedic Filler

[0161] This preparation can be used to fill extraction sockets,periodontal defects, orthopedic defects, root canals, and screw channelsfollowing fracture repair, etc. Porosity allows the penetration of cellssuch as osteocytes. Bioactive agents such as anti-infectives andosteogenic compounds can be included to promote bone resorption in asterile environment as the matrix is resorbed.

[0162] Component A=Ca(H₂PO₄)₂/NaHCO₃ (1/1)

[0163] Component B=Calcium sulfate-hemihydrate

[0164] Component C=Biopolymer solution, e.g., Solution D from Example 13

[0165] Component A (0.1-0.3 g) and Component B (0.7-0.9) are thoroughlymixed (total=1 g). This solid mixture is then blended with 0.6 ml ofbiopolymer solution. The slurry is immediately injected and allowed tosolidify in situ. Amikacin sulfate (50-100 mg) can be included as theantibiotic.

Example 16

[0166] Preparation of Sterile Amikacin Matrix

[0167] Calcium sulfate-hemihydrate is sterilized by dry heat—120° for 4hrs. Solution A is prepared as follows. Dextran sulfate (1g/CAS9011-18-1) is dissolved in 10 ml of water along with 3 g ofamikacin sulfate (CAS 39833-55-5). The solution is filtered (0.2 micronfilter) into sterile serum cap vials. To 1 g of calciumsulfate-hemihydrate is added 0.5-0.7 ml of Solution A. The componentsare mixed thoroughly to produce a uniform slurry. The slurry can beinjected directly into the patient, injected into a mold, or used toproduce microbeads. Operations including mixing and beyond are conductedis a sterile space. Molds for 3-mm beads are sterilized by ethyleneoxide treatment. Milling equipment is sterilized by autoclaving or bytreatment with ethylene oxide.

Example 17

[0168] Treatment of Equine Joint Sepsis

[0169] Infection of the equine joint is characterized by heat, swelling,pain on palpation/flexion, and lameness. The use of amikacin beads ispreceded by through-and-through lavage or other joint drainage/flushingtechnique. Amikacin beads are suspended in lactated Ringer's solutionand injected. i.a., with an 18 ga needle. Dosages range from 100-500 mg.Systemic antibiotics may be used as an adjunct. Culture to showsusceptibility is obviously desirable. If amikacin beads are notindicated, cefazolin matrix beads may be employed. Larger beads, 3 mm,can be placed within the joint capsule using the arthroscope or acannula.

[0170] Representative results with amikacin beads (100 mg) are asfollows:

[0171] Case 1. Luxated LR fetlock with exposure of distal M3. Priortreatment consisting of extensive joint flushing, and systemicantibiotic treatment was unsuccessful—persistent positive cultures forStaph, and Strep. Injection of 100 mg of amikacin beads resulted inresolution of the infected condition—no more flaring, heat, or positivecultures. Horse returned to sound condition.

[0172] Case 2. Puncture wound of the RR fetlock resulted in sepsis ofthe tendon sheath. Surgery including annular resection systemicantibiotic therapy did not result in correcting the condition. Amikacinbeads were injected and infection (Staph.) was eradicated as judged byculture and symptoms. Horse returned to sound condition.

[0173] Case 3. Puncture wound of left hock joint resulting in aninfection. Horse was treated immediately with amikacin microbeads andthe treatment repeated after one week. Infection was resolved; horsereturned to training.

[0174] It will be readily apparent to those skilled in the art thatnumerous modifications and additions may be made to both the presentinvention, the disclosed device, and the related system withoutdeparting from the invention disclosed.

1-67. (Canceled)
 68. A solid composition for the controlled release ofan active agent comprising an active agent and a matrix polymerdispersed throughout a solid calcium phosphate matrix, wherein saidcomposition is the hydration reaction product of a mixture comprised of:a) the active agent, b) calcium phosphate, and c) a matrix polymerand/or complexing agent which slows the release of said active agentfrom said solid matrix.
 69. A solid composition as in claim 68 whereinsaid composition is in the form of a bead, wafer, tablet, sphere,granule or cylinder.
 70. A solid composition as in claim 68 wherein thematrix polymer is selected from the group consisting of hyaluronic acid,dextran, and protein.
 71. A solid composition as in claim 68 wherein thematrix polymer is selected from the group consisting of polyethyleneglycol, polyvinylpyrrolidone, polyvinylalcohol, starch, zanthan,cellulose and cellulose derivatives.
 72. A solid composition as in claim68 wherein the complexing agent is selected from the group consisting ofdextran sulfate, chondroitin sulfate, polyglutamic acid, polyasparticacid, polynucleotides, a cationic polypeptide,cyclodextrin, pentosanpolysulfate, cyclodextrins, polyoxyethylene alcohol, ester or ether, anddefatted albumin.
 73. A solid composition for the controlled release ofan active agent comprising: (a) an active agent; (b) calcium sulfate orphosphate; and (c) a matrix polymer which slows the release of saidactive agent, wherein said composition is a solid matrix due tohydration of calcium sulfate or phosphate in an aqueous mixture of saidactive agent, said matrix polymer and said calcium sulfate or phosphate,and wherein said composition is in the form of a bead, wafer, tablet,sphere granule or cylinder.
 74. A solid composition for the controlledrelease of an active agent consisting of: (a) an active agent; (b)calcium sulfate or phosphate; and (c) a matrix polymer which slows therelease of said active agent, wherein said composition is a solid matrixdue to hydration of calcium sulfate or phosphate in an aqueous mixtureof said active agent, said matrix polymer and said calcium sulfate orphosphate.
 75. A solid composition for the controlled release of anactive agent comprising: (a) an active agent; (b) calcium sulfate orphosphate; and (c) polyethylene glycol, wherein said composition is asolid matrix due to hydration of calcium sulfate or phosphate in anaqueous mixture of said active agent, said polyethylene glycol and saidcalcium sulfate or phosphate.
 76. A solid composition for the controlledrelease of an active agent comprising: (a) an active agent; (b) calciumsulfate or phosphate; and (c) dextran sulfate, wherein said compositionis a solid matrix due to hydration of calcium sulfate or phosphate in anaqueous mixture of said active agent, said dextran sulfate and saidcalcium sulfate or phosphate.
 77. A solid composition for the controlledrelease of an active agent comprising an active agent which is dispersedthroughout a solid matrix reaction product of an aqueous mixturecomprised of: (a) an active agent, (b) calcium sulfate or phosphate, (c)a matrix polymer in an amount sufficient to slow the release of saidactive agent, and (d) water in an amount sufficient to form a solidmatrix due to the hydration of said calcium sulfate or phosphate,wherein said composition is in the form of a bead, wafer, tablet,sphere, granule or cylinder.
 78. A solid composition for the controlledrelease of an active agent comprising: (a) an active agent; (b) calciumsulfate or phosphate; (c) a matrix polymer which slows the release ofsaid active agent, and (d) a salt of a fatty acid; wherein saidcomposition is a solid matrix due to hydration of calcium sulfate orphosphate in an aqueous mixture of said active agent, said matrixpolymer and said calcium sulfate or phosphate.
 79. A solid compositionfor the controlled release of an active agent comprising an active agentwhich is dispersed throughout a solid matrix reaction product of anaqueous mixture comprised of: (a) an active agent, (b) calcium sulfateor phosphate, (c) a matrix polymer in an amount sufficient to slow therelease of said active agent, (d) water in an amount sufficient to forma solid matrix due to the hydration of said calcium sulfate orphosphate, and (e) a salt of a fatty acid.
 80. The solid composition ofany one of claims 78-79, wherein said salt of a fatty acid comprisescalcium stearate.
 81. A method of producing sustained release of anactive agent in a mammal comprising administering to said mammal a solidcomposition comprising an active agent which is dispersed throughout asolid matrix reaction product of an aqueous mixture comprised of a)active agent, b) calcium phosphate, c) a matrix polymer, and/or acomplexing agent.
 82. A method as in claim 81 wherein said active agentis an antiinfective.
 83. A method as in claim 82, further comprising achondroprotective agent.
 84. A method as in claim 81 wherein said activeagent is an antineoplastic agent.
 85. A method as in claim 81, whereinsaid active agent is an antiinflammatory agent.
 86. A method ofscaffolding bone or filling a defect in bone comprising administering tosaid bone a composition comprising: calcium phosphate; and a matrixpolymer and/or complexing agent which slows the release of said activeagent, wherein said composition becomes a solid matrix due to hydrationof calcium phosphate in an aqueous mixture of said active agent, saidmatrix polymer and/or complexing agent and said calcium phosphate.
 87. Amethod as in any one of claims 81-86, wherein the solid matrix furthercomprises a salt of a fatty acid.
 88. A method as in claim 87, whereinthe salt of a fatty acid comprises calcium stearate.